1. Field of the Invention
The present invention relates to a method of treating or preventing an inflammatory bowel disease in a subject by administering cholera toxin B subunit (CT-B) to the subject. Further provided are methods for treating or preventing inflammation and/or an autoimmune disorder in a subject and for decreasing interferon gamma (IFN-γ) and/or interleukin 12 (IL-12) activity in a subject by administering CT-B to the subject.
2. Background Art
Inflammatory bowel disease (IBD), encompassing Crohn's disease (CD) and ulcerative colitis (UC), is an idiopathic chronic disease occurring with increasing frequency in Western populations (1, 2). Various animal models of chronic intestinal inflammation have been established which have provided new insights into the pathogenesis of IBD (3). These include mice carrying transgenes of HLA-B27 and β2-microglobulin (4) and mice in which the genes for interleukin-2 (IL-2) (5), interleukin-10 (IL-10) (6) and the alpha or beta chain of the T cell receptor (7) have been inactivated by homologous recombination. In addition, a colitis model has been recently established by the adoptive transfer of normal CD45RBhi T cells from BALB/c mice to C.B.-17 scid mice, wherein the transferred T cells manifest a Th1 cytokine response associated with granulomatous inflammation. This experimental colitis can be prevented by systemic administration of anti-interferon-gamma (anti-IFN-γ) (two doses) and by systemic, daily administration of recombinant IL-10 (rIL-10), given at the same time disease is induced, but not with recombinant interleukin-4 (rIL-4) (8). The observation that administration of IL-10, a product of Th2 cell differentiation, but not IL-4, which is also a product of Th2 cell differentiation, can prevent experimental colitis, underscores the unpredictability of administering cytokines to prevent or treat IBD.
The intrarectal instillation of the hapten agent, 2,4,6-trinitrobenzene sulfonic acid (TNBS) in SJL mice results in a colitis that resembles many features of human Crohn's disease. In particular, histologic analysis reveals a colitis that is transmural in nature and associated with granuloma formation. In addition, studies of the genesis of the immune response to the rectal administration of TNBS have shown that lesional T cells produce significantly increased amounts of IFN-γ and reduced amounts of interleukin-4 (IL-4) and lesional antigen presenting cells (APC) produce increased amounts of IL-12. These findings indicate that the colitis occurring in these mice is due to a dysregulated Th1-mediated immune response (9).
Cholera holotoxin (CT) is composed of a monomeric “A” subunit bound to five identical “B” subunits. The A subunit (CT-A) affects G protein signaling activity by inhibiting adenylate cyclase while the B subunit (CT-B) facilitates the entry of the A subunit into the cell by binding to GM 1 ganglioside on the cell surface. The ability of the holotoxin to act as a potent immunogen and mucosal adjuvant (10–12) has largely been attributed to subunit A, but recent evidence indicates that CT-B also has immunogenic effects. In particular, it appears that CT-B can also act as a mucosal adjuvant, at least under certain circumstances (13–15). In addition, oral administration of antigen coupled to recombinant CT-B (rCT-B) potentiates the induction of oral tolerance to the coupled antigen. Because in this case, the CT-B must be coupled to the antigen to have an effect, CT-B may be acting through its capacity to focus antigen on lymph cells rather than act as an immunomodulator (16–19). However, the effect of CT-B coupled to antigen is antigen-specific and thus has no polyclonal effect on the immune function.
The present invention overcomes previous shortcomings in the treatment of autoimmune disorders such as IBD by providing methods of treating or preventing autoimmune disease such as IBD by the administration of cholera toxin subunit B to a subject in need of such treatment. The administration of cholera toxin subunit B to a subject by the methods of this invention can also treat or prevent inflammation and reduce the activity of IL-12 and IFN-γ.